Pharmaceutical formulations for dry powder inhalers in the form of hard-pellets

ABSTRACT

The invention provides a formulation to be administered as dry powder for inhalation suitable for efficacious delivery of active ingredients into the low respiratory tract of patients suffering of pulmonary diseases such as asthma. In particular, the invention provides a formulation to be administered as dry powder for inhalation freely flowable, which can be produced in a simple way, physically and chemically stable and able of delivering either accurate doses and high fine particle fraction of low strength active ingredients by using a high- or medium resistance device.

PRIOR ART

Inhalation anti-asthmatics are widely used in the treatment ofreversible airway obstruction, inflammation and hyperresponsiveness.

Presently, the most widely used systems for inhalation therapy are thepressurised metered dose inhalers (MDIs) which use a propellant to expeldroplets containing the pharmaceutical product to the respiratory tract.

However, despite their practicality and popularity, MDIs have somedisadvantages:

-   i) droplets leaving the actuator orifice could be large or have an    extremely high velocity resulting in extensive oropharyngeal    deposition to the detriment of the dose which penetrates into the    lungs; the amount of drug which penetrates the bronchial tree may be    further reduced by poor inhalation technique, due to the common    difficulty of the patient to synchronise actuation form the device    with inspiration;-   ii) chlorofluorocarbons (CFCs), such as freons contained as    propellants in MDIs, are disadvantageous on environmental grounds as    they have a proven damaging effect on the atmospheric ozone layer.

Dry powder inhalers (DPIs) constitute a valid alternative to MDIs forthe administration of drugs to airways. The main advantages of DPIs are:

-   i) being breath-actuated delivery systems, they do not require    co-ordination of actuation since release of the drug is dependent on    the patient own inhalation;-   ii) they do not contain propellants acting as environmental hazards;-   iii) the velocity of the delivered particles is the same or lower    than that of the flow of inspired air, so making them more prone to    follow the air flow than the faster moving MDI particles, thereby    reducing upper respiratory tract deposition.    DPIs can be Divided into Two Basic Types:-   i) single dose inhalers, for the administration of pre-subdivided    single doses of the active compound;-   ii) multidose dry powder inhalers (MDPIs), either with    pre-subdivided single doses or pre-loaded with quantities of active    ingredient sufficient for multiple doses; each dose is created by a    metering unit within the inhaler.

On the basis of the required inspiratory flow rates (1/min) which inturn are strictly depending on their design and mechanical features,DPI's are also divided in:

-   i) low-resistance devices (>90/min);-   ii) medium-resistance devices (about 60 1/min);-   iii) high-resistance devices (about 30 1/min).

The reported flow rates refer to the pressure drop of 4 KPa (KiloPascal)in accordance to the European Pharmacopoeia (Eur Ph).

Drugs intended for inhalation as dry powders should be used in the formof micronised powder so they are characterised by particles of fewmicrons (μm) particle size. Said size is quantified by measuring acharacteristic equivalent sphere diameter, known as aerodynamicdiameter, which indicates the capability of the particles of beingtransported suspended in an air stream. Hereinafter, we consider asparticle size the mass median aerodynamic diameter (MMAD) whichcorresponds to the aerodynamic diameter of 50 percent by weight of theparticles. Respirable particles are generally considered to be thosewith diameters from 0.5 to 6 μm, as they are able of penetrating intothe lower lungs, i.e. the bronchiolar and alveolar sites, whereabsorption takes place. Larger particles are mostly deposited in theoropharyngeal cavity so they cannot reach said sites, whereas thesmaller ones are exhaled.

Although micronisation of the active drug is essential for depositioninto the lower lungs during inhalation, it is also known that the finerare the particles, the stronger are the cohesion forces. Strong cohesionforces hinder the handling of the powder during the manufacturingprocess (pouring, filling). Moreover they reduce the flowability of theparticles while favouring the agglomeration and/or adhesion thereof tothe walls. In multidose DPI's, said phenomena impair the loading of thepowder from the reservoir to the aerosolization chamber, so giving riseto handling and metering accuracy problems.

Poor flowability is also detrimental to the respirable fraction of thedelivered dose being the active particles unable to leave the inhalerand remaining adhered to the interior of the inhaler or leaving theinhaler as large agglomerates; agglomerated particles, in turn, cannotreach the bronchiolar and alveolar sites of the lungs. The uncertaintyas to the extent of agglomeration of the particles between eachactuation of the inhaler and also between inhalers and different batchesof particles, leads to poor dose reproducibility as well.

In the prior art, one possible method of improving the flowingproperties of these powders is to agglomerate, in a controlled manner,the micronised particles to form spheres of relatively high density andcompactness. The process is termed spheronisation while the roundparticles formed are called pellets. When, before spheronisation, theactive ingredient is mixed with a plurality of fine particles of one ormore excipient, the resulting product has been termed as soft pellets.

Otherwise powders for inhalation could be formulated by mixing themicronised drug with a carrier material (generally lactose, preferablyαlactose monohydrate) consisting of coarser particles to give rise toso-called ‘ordered mixtures’.

However, either ordered mixtures and pellets should be able toeffectively release the drug particles during inhalation, in order toallow them to reach the target site into the lungs.

At this regard, it is well known that the interparticle forces whichoccur between the two ingredients in the ordered mixtures may turn outto be too high thus preventing the separation of the micronised drugparticles from the surface of the coarse carrier ones during inhalation.The surface of the carrier particles is, indeed, not smooth but hasasperities and clefts, which are high energy sites on which the activeparticles are preferably attracted to and adhere more strongly. Inaddition, ordered mixtures consisting of low strength active ingredientscould also face problems of uniformity of distribution and hence ofmetering accurate doses.

On the other hand, soft pellets may reach a so high internal coherenceas to compromise their breaking up into the small particles duringinhalation; such drawback could be regarded as a particular criticalstep when high-resistance dry powder inhalers are used. With saidinhalers, less energy is indeed available for breaking up the pelletsinto the small primary particles of the active ingredient. The softpellets may also face some problems of handling during filling and useof the inhalers.

In consideration of all problems and disadvantages outlined, it would behighly advantageous to provide a formulation aimed at delivering lowstrength active ingredients after inhalation with a DPI device,preferably a high-resistance one and exhibiting: i) good uniformity ofdistribution of the active ingredient; ii) small drug dosage variation(in other words, adequate accuracy of the delivered doses); iii) goodflowability; iv) adequate physical stability in the device before use;v) good performance in terms of emitted dose and fine particle fraction(respirable fraction).

Another requirement for an acceptable formulation is its adequateshelf-life.

It is known that the chemical compounds can undergo chemico-physicalalterations such as amorphisation, when subjected to mechanicalstresses. Amorphous or partially amorphous materials, in turn, absorbwater in larger amounts than crystalline ones (Hancock et al. J. Pharm.Sci. 1997, 86, 1-12) so formulations containing active ingredients,whose chemical stability is particularly sensitive to the humiditycontent, will benefit during their preparation by the use of as low aspossible energy step treatment.

Therefore, it would be highly advantageous to provide a process forpreparing said formulation in which a low energy step is envisionedduring the incorporation of the active ingredient to the mixture in sucha way to ensure adequate shelf life of the formulation suitable forcommercial distribution, storage and use.

OBJECT OF THE INVENTION

It is an object of the invention to provide a formulation to beadministered as a dry powder for inhalation suitable for efficaciousdelivery of low strength active ingredients into the low respiratorytract of patients suffering from pulmonary diseases such as asthma. Inparticular, it is an object of the invention to provide a formulation tobe administered as a dry powder for inhalation, which is freelyflowable, which can be produced in a simple way, which is physically andchemically stable and is capable of delivering either accurate does anda high fine particle fraction of the following active ingredients:

long acting β2-agonists belonging to the formula sketched below

wherein R is preferably 1-formylamino-2-hydroxy-phen-5-yl (formoterol)or 8-hydroxy-2(1H)-quinolinon-5-yl (TA 2005) and its stereoisomers andtheir salts;

-   -   a corticosteroid selected from budesonide and its epimers,        preferably its 22R epimer;    -   their mixture and their combination with other active        ingredients such as for example beclomethasone dipropionate.        According to a first embodiment of the invention there is        provided a powdery formulation comprising: i) a fraction of fine        particle size constituted of a mixture of a physiologically        acceptable excipient and magnesium stearate, the mixture having        a mean particle size of less than 35 μm; ii) a fraction of        coarse particles constituted of a physiologically acceptable        carrier having a particle size of at least 90 μm , said mixture        being composed of 90 to 99 percent by weight of the particles of        excipient and 1 to 10 percent by weight of magnesium stearate        and the ratio between the fine excipient particles and the        coarse carrier particles being between 1:99 and 40:60 percent by        weight; and the said mixture having been further mixed with the        active ingredients mentioned above in micronised form or        combination thereof.

In a preferred embodiment of the invention, the magnesium stearateparticles partially coat the surface of either the excipient particlesand the coarse carrier particles. Said feature could be achieved byexploiting the peculiar film forming properties of such water-insolubleadditive, as also reported in the co-pending application WO 00/53157 ofChiesi. The coating can be established by scanning electron microscopeand the degree of coating can be evaluated by means of the imageanalysis method.

It has been found indeed that the single features of adding either of afraction with a fine particle size of the physiologically acceptableexcipient or magnesium stearate is not enough for guaranteeing high fineparticle doses of the aforementioned active ingredients upon inhalationin particular by a high-resistance device. For significantly improvingthe aerosol performances, it is necessary that both said excipient witha suitable particle size fraction should be present in the formulationand that the magnesium stearate particles should, at least partially,coat the surface of either the excipient and the coarse carrierparticles.

Moreover, it has been found that the particle size of thephysiologically acceptable excipient, the main component of the mixturei) is of particular importance and that the best results in terms ofaerosol performances are achieved when its particle size is less than 35μm, preferably less than 30, more preferably less than 20, even morepreferably less than 15 μm.

In a more preferred embodiment , the formulation of the invention is inthe form of ‘hard pellets’ and they are obtained by subjecting themixture to a spheronisation process.

By the term of ‘hard pellets’ we mean spherical or semi-spherical unitswhose core is made of coarse particles. The term has been coined fordistinguishing the formulation of the invention from the soft pellets ofthe prior art which are constituted of only microfine particles (WO95/24889, GB 1520247, WO 98/31353).

By the term ‘spheronisation’ we mean the process of rounding off of theparticles which occurs during the treatment.

In an even more preferred embodiment of the invention, the coarsecarrier particles have a particle size of at least 175 μm as well as ahighly fissured surface. A carrier of the above mentioned particle sizeis particularly advantageous when the fine excipient particlesconstitute at least the 10 percent by weight of the final formulation.

It has been found that, whereas formulations containing conventionalcarriers and having fine particle contents of above 10% tend to havepoor flow properties, the formulations according to the invention haveadequate flow properties even at fines contents (that is contents ofactive particles and of fine excipient particles) of up to 40 percent byweight.

The prior art discloses several approaches for improving the flowabilityproperties and the respiratory performances of low strength activeingredients. WO 98/31351 claims a dry powder composition comprisingformoterol and a carrier substance, both of which are in finely dividedform wherein the formulation has a poured bulk density of from 0.28 to0.38 g/ml. Said formulation is in the form of soft pellet and does notcontain any additive.

EP 441740 claims a process and apparatus thereof for agglomerating andmetering non-flowable powders preferably constituted of micronisedformoterol fumarate and fine particles of lactose (soft pellets).

Furthermore several methods of the prior art were generally addressed atimproving the flowability of powders for inhalation and/or reducing theadhesion between the drug particles and the carrier particles.

-   -   GB 1,242,211, GB 1,381,872 and GB 1,571,629 disclose        pharmaceutical powders for the inhalatory use in which the        micronised drug (0.01-10 μm) is respectively mixed with carrier        particles of sizes 30 to 80 μm, 80 to 150 μm, and less than 400        μm wherein at least 50% by weight of which is above 30 μm.    -   WO 87/05213 describes a carrier, comprising a conglomerate of a        solid water-soluble carrier and a lubricant, preferably 1%        magnesium stearate, for improving the technological properties        of the powder in such a way as to remedy to the reproducibility        problems encountered after the repeated use of a high resistance        inhaler device.    -   WO 96/02231 claims a mixture characterised in that the        micronised active compound is mixed with rough carrier particles        having a particle size of 400 μm to 1000 μm. According to a        preferred embodiment of the invention, the components are mixed        until the carrier crystals are coated with the fine particles        (max. for 45 minutes). No example either with auxiliary        additives and/or with low strength active ingredient is        reported.    -   EP 0,663,815 claims the addition of finer particles (<10 μm) to        coarser carrier particles (>20 μm) for controlling and        optimising the amount of delivered drug during the        aerosolisation phase.    -   WO 95/11666 describes a process for modifying the surface        properties of the carrier particles by dislodging any asperities        in the form of small grains without substantially changing the        size of the particles. Said preliminary handling of the carrier        causes the micronised drug particles to be subjected to weaker        interparticle adhesion forces.    -   In WO 96/23485, carrier particles are mixed with an        anti-adherent or anti-friction material consisting of one or        more compounds selected from amino acids (preferably leucine);        phospholipids or surfactants; the amount of additive and the        process of mixing are preferably chosen in such a way as to not        give rise to a real coating. It appears that the presence of a        discontinuous covering as opposed to a “coating” is an important        and advantageous feature. The carrier particles blended with the        additive are preferably subjected to the process disclosed in WO        95/11666.    -   Kassem (London University Thesis 1990) disclosed the use of        relatively high amount of magnesium stearate (1.5%) for        increasing the ‘respirable’ fraction. However, the reported        amount is too great and reduces the mechanical stability of the        mixture before use.    -   WO 00/28979 is addressed to the use of small amounts of        magnesium stearate as additive for improving the stability to        the humidity of dry powder formulations for inhalation.    -   WO 00/33789 refers to an excipient powder for inhalable drugs        comprising a coarse first fraction (with at least 80% by weight        having a particle size of at least 10 μm), a fine second        fraction (with at least 90% by weight having a particle size of        no more than 10 μm) and a ternary agent which is preferably a        water-soluble surface-active agent with a preference for        leucine.

In none of aforementioned documents the features of the formulation ofthe invention are disclosed and none of the teaching therein disclosedcontributes to the solution of the problem according to the invention.All the attempts of obtaining stable powder formulations of low strengthactive ingredients endowed of good flowability and high fine particlefraction according to some of the teaching of the prior art, for exampleby preparation of ordered mixture, addition of a fine fraction, mereaddition of additives, were indeed unsuccessful as demonstrated by theexamples reported below. In particular, in the prior art it oftenoccurred that the solutions proposed for a technical problem (i.e.improving dispersion of the drug particles) was detrimental to thesolution of another one (i.e. improving flowability, mechanicalstability) or vice versa.

On the contrary, the formulation of the invention shows either excellentTheological properties and physical stability and good performances interms of fine particle fraction , preferably more than 40%. Thecohesiveness between the partners has been indeed adjusted in such a wayas to give sufficient adhesion force to hold the active particles to thesurface of the carrier particles during manufacturing of the dry powderand in the delivery device before use, but to allow the effectivedispersion of the active particles in the respiratory tract even in thepresence of a poor turbulence as that created by high-resistancedevices.

Contrary to what has been stated in the prior art (EP 441740), in theformulation of the invention the presence of an additive with lubricantproperties such as magnesium stearate, in a small amount, does notcompromise the integrity of the pellets before use.

According to a second embodiment of the invention there are alsoprovided processes for making the formulation of the invention, in sucha way as that the magnesium stearate particles partially coat thesurface of either the excipient particles and the coarse carrierparticles with a degree of coating that can vary depending on the amountand particle size of the fine fraction and, in any case, is of at least5%, preferably at least 15%.

According to a particular embodiment, there is provided a processincluding the steps of: i) co-micronising the excipient particles andthe magnesium stearate particles such that to reduce their particle sizebelow 35 μm, and contemporaneously making the additive particlespartially coating the surface of the excipient particles; ii)spheronising by mixing the resulting mixture with the coarse carrierparticles such that mixture particles adhere to the surface of thecoarse carrier particles; iii) adding by mixing the active particles tothe spheronised particles.

According to a further particular embodiment of the invention there isprovided another process, said process including the steps of: i) mixingthe excipient particles in the micronised form and the magnesiumstearate particles in such a way as to make the additive particlespartially coating the surface of the excipient particles; ii)spheronising by mixing the resulting mixture with the coarse carrierparticles such that mixture particles adhere to the surface of thecoarse carrier particles; iii) adding by mixing the active particles tothe spheronised particles.

When the coarse carrier particles have a particle size of at least 175μm and in a preferred embodiment a highly fissured surface, theformulation of the invention could also be prepared by: i) co-mixing thecoarse carrier particles, magnesium stearate and the fine excipientparticles for not less than two hours;

-   ii) adding by mixing the active particles to the mixture.

It has been indeed found that the particles need to be processed for atleast two hours in order to either have a good fine particle fraction(respirable fraction) and no problem of sticking during the preparation.

In all process claimed, contrary to the prior art (WO 98/31351), theactive ingredient is uniformly incorporated in the mixture by simplemixing so avoiding any potential mechanical stress which may disturb thecristallinity of its particles.

Advantageously, the coarse and fine carrier particles may be constitutedof any pharmacologically acceptable inert material or combinationthereof; preferred carriers are those made of crystalline sugars, inparticular lactose; the most preferred are those made of α-lactosemonohydrate. Advantageously the diameter of the coarse carrier particlesis at least 100 μm, more advantageously at least 145 μm, preferably atleast 175 μm, more preferably between 175 and 400 μm, even morepreferably between 210 and 355 μm.

When the diameter of the coarse carrier particles is at least 175 μm,the carrier particles have preferably a relatively highly fissuredsurface, that is, on which there are clefts and valleys and otherrecessed regions, referred to herein collectively as fissures.

The expression “relatively highly fissured” is used herein to mean thatthe ratio of a theoretical envelope volume of the particles, ascalculated from the envelope of the particles, to the actual volume ofthe particles, that is, the volume defined by the actual surface of theparticles (that ratio hereafter being referred to as the “fissureindex”), is at least 1.25. The theoretical envelope volume may bedetermined optically, for example, by examining a small sample of theparticles using an electron microscope. The theoretical envelope volumeof the particles may be estimated via the following method. An electronmicrograph of the sample may be divided into a number of grid squares ofapproximately equal populations, each containing a representative sampleof the particles. The population of one or more grids may then beexamined and the envelope encompassing each of the particles determinedvisually as follows. Measure the Feret's diameter for each of theparticles with respect to a fixed axis . The Feret's diameter forparticles within a grid is measured relative to a fixed axis of theimage, typically at least ten particles are measured for their Feret'sdiameter. Feret's diameter is defined as the length of the projection ofa particle along a given reference line as the distance between theextreme left and right tangents that are perpendicular to the referenceline. A mean Feret's diameter is derived. A theoretical mean envelopevolume may then be calculated from this mean diameter to give arepresentative value for all the grid squares and thus the whole sample.Division of that value by the number of particles gives the mean valueper particle. The actual volume of the particles may then be calculatedas follows. The mean mass of a particle is calculated as follows. Take asample of approximately 50 mg, record the precise weight to 0.1 mg .Then by optical microscopy determine the precise number of particles inthat sample. The mean mass of one particle can then be determined.Repeat this five times to obtain a mean value of this mean.

Weigh out accurately a fixed mass of particles (typically 50 g),calculate the number of particles within this mass using the above meanmass value of one particle. Immerse the sample of particles in a liquidin which the particles are insoluble and, after agitation to removetrapped air, measuring the amount of liquid displaced. From thiscalculate the mean actual volume of one particle.

The fissure index is advantageously not less than 1.5, and is, forexample, 2 or more.

An alternative method of determining whether carrier particles haveappropriate characteristics is to determine the rugosity coefficient.The “rugosity coefficient” is used to mean the ratio of the perimeter ofa particle outline to the perimeter of the “convex hull”. This measurehas been used to express the lack of smoothness in the particle outline.The “convex hull” is defined as a minimum enveloping boundary fitted toa particle outline that is nowhere concave. (See “The Shape ofPowder-Particle Outlines” A. E. Hawkins, Wiley 1993). The “rugositycoefficient” may be calculated optically as follows. A sample ofparticles should be identified from an electron micrograph as identifiedabove. For each particle the perimeter of the particle outline and theassociated perimeter of the “convex hull” is measured to provide the“rugosity coefficient”. This should be repeated for at least tenparticles to obtain a mean value. The mean “rugosity coefficient” is atleast 1.25.

The additive is magnesium stearate. Advantageously, the amount ofmagnesium stearate in the final formulation is comprised between atleast 0.02 and not more than 1.5 percent by weight (which equates to 1.5g per 100 g of final formulation), preferably at least 0.05 and not morethan 1.0 percent by weight, more preferably between 0.1 and not morethan 0.6 percent by weight, even more preferably between 0.2 and 0.4percent by weight.

According to the invention the fraction with a fine particle size iscomposed of 90 to 99 percent by weight of the physiologically acceptableexcipient and 1 to 10 percent by weight of magnesium stearate and theratio between the fraction of fine particle size and the fraction ofcoarse carrier particle is comprised between 1:99 and 40:60 percent byweight, preferably between 5:95 and 30:70 percent by weight, even morepreferably between 10:90 and 20:80 percent by weight.

In a preferred embodiment of the invention, the fraction with a fineparticle size is composed of 98 percent by weight of α-lactosemonohydrate and 2 percent by weight of magnesium stearate and the ratiobetween the fraction with a fine particle size and the coarse fractionmade of α-lactose monohydrate particles is 10:90 percent by weight,respectively.

Advantageously the formulation of the invention has an apparent densitybefore settling of at least 0.5 g/ml, preferably from 0.6 to 0.7 g/mland a Carr index of less than 25, preferably less than 15.

In one of the embodiment of the invention, the excipient particles andmagnesium stearate particles are co-micronised by milling,advantageously in a ball mill for at least two hours, preferably untilthe final particle size of the mixture is less than 35 μm, preferablyless than 30 μm, more preferably less than 15 μm. In a more preferredembodiment of the invention the particles are co-micronised by using ajet mill.

Alternatively, the mixture of the excipient particles with a startingparticle size less than 35 μm, preferably less than 30 μm, morepreferably less than 15 μm, with the magnesium stearate particles willbe prepared by mixing the components in a high-energy mixer for at least30 minutes, preferably for at least one hour, more preferably for atleast two hours.

In a general way, the person skilled in the art will select the mostproper size of the fine excipient particles either by sieving or bysuitably adjusting the time of co-milling.

The spheronisation step will be carried out by mixing the coarse carrierparticles and the fine particle fraction in a suitable mixer, e.g.tumbler mixers such as Turbula, rotary mixers or instant mixer such asDiosna for at least 5 minutes, preferably for at least 30 minutes, morepreferably for at least two hours, even more preferably for four hours.In a general way, the person skilled in the art will adjust the time ofmixing and the speed of rotation of the mixer to obtain homogenousmixture.

When the formulation of the invention is prepared by co-mixing thecoarse carrier particles, magnesium stearate and the fine excipientparticles all together, the process is advantageously carried out in asuitable mixer, preferably in a Turbula mixer for at least two hours,preferably for at least four hours.

The ratio between the spheronised carrier and the drug (the activeingredient) will depend on the type of inhaler device used and therequired dose.

The mixture of the spheronised carrier with the active particles will beprepared by mixing the components in suitable mixers like those reportedabove.

Advantageously, at least 90% of the particles of the drug have aparticle size less than 10 μm, preferably less than 6 μm.

The process of the invention is illustrated by the following examples.

EXAMPLE 1 Hard-Pellet Formulation Containing Coarse Lactose (CapsuLac212-355 μm), a Micronized Pre-Blend Lactose/Magnesium Stearate MixtureObtained by Jet Milling and Formoterol Fumarate as Active Ingredient

a) Preparation of the Formulation

α-Lactose monohydrate SpheroLac 100 (Meggle EP D30) with a startingparticle size of 50 to 400 μm (d(v, 0.5) of about 170, m) and magnesiumstearate with a starting particle size of 3 to 35 μm (d(v, 0.5) of about10 μm) in the ratio 98:2 percent by weight were co-milled in a jet millapparatus. At the end of the treatment, a significant reduction of theparticle size was observed (blend A).

85 percent by weight of α-lactose monohydrate CapsuLac (212-355 μm) wasplaced in a 240 ml stainless steel container, then 15 percent by weightof blend A was added. The blend was mixed in a Turbula mixer for 2 hoursat 42 r.p.m (blend B).

Micronised formoterol fumarate was added to the blend B and mixed in aTurbula mixer for 10 mins at 42 r.p.m. to obtain a ratio of 12 μg ofactive to 20 mg of carrier; the amount of magnesium stearate in thefinal formulation is 0.3 percent by weight. The final formulation (hardpellet formulation) was left to stand for 10 mins then transferred toamber glass jar.

b) Characterisation of the Micronised Mixture (Blend A)

The micronized mixture (blend A) was characterised by particle sizeanalysis (Malvern analysis), water contact angle and degree of molecularsurface coating calculated according to Cassie et al. in Transaction ofthe Faraday Society 40; 546,1944.

The results obtained are reported in Table 1.

TABLE 1 Micronised mixture (blend A) Particle size distribution (μm)Malvern d (v, 0.1) 1.58 d (v, 0.5) 4.19 d (v, 0.9) 9.64 Water contactangle   40° Degree of coating   15% * * α-Lactose monohydrate watercontact angle 12°; magnesium stearate water contact angle 118°c) Chemical and Technological Characterisation of the Hard-PelletFormulation

The formulation mixture was characterised by its density/flowabilityparameters and uniformity of distribution of the active ingredient. Theapparent volume and apparent density were tested according to the methoddescribed in the European Pharmacopoeia (Eur. Ph.). Powder mixtures (100g) were poured into a glass graduated cylinder and the unsettledapparent volume V₀ is read; the apparent density before settling (dv)was calculated dividing the weight of the sample by the volume V₀ After1250 taps with the described apparatus, the apparent volume aftersettling (V₁₂₅₀) is read and the apparent density after settling (ds)was calculated.

The flowability properties were tested according to the method describedin the Eur. Ph.

Powder mixtures (about 110 g) were poured into a dry funnel equippedwith an orifice of suitable diameter that is blocked by suitable mean.The bottom opening of the funnel is unblocked and the time needed forthe entire sample to flow out of the funnel recorded. The flowability isexpressed in seconds and tenths of seconds related to 100 g of sample.

The flowability was also evaluated from the Carr's index calculatedaccording to the following formula:${{{Carr}'}s\quad{index}\quad(\%)} = {\frac{{\mathbb{d}s} - {\mathbb{d}v}}{\mathbb{d}s} \times 100}$

A Carr index of less than 25 is usually considered indicative of goodflowability characteristics.

The uniformity of distribution of the active ingredient was evaluated bywithdrawing 10 samples, each equivalent to about a single dose, fromdifferent parts of the blend. The amount of active ingredient of eachsample was determined by High-Performance Liquid Chromatpgraphy (HPLC).

The results are reported in Table 2.

TABLE 2 Chemical and Technological Parameters of the hard pelletformulation Apparent volume/density App. volume (V₀) before settling 156 ml App. density (d_(v)) before settling 0.64 g/ml App. volume(V₁₂₅₀) after settling  138 ml App. density (d_(s)) after settling 0.73g/ml Flowability Flow rate through 4 mm Ø  152 s/100 g Carr Index   12Uniformity of distribution of active ingredient Mean Value 12.1 μg RSD 2.2%

-   -   d) Determination of the Aerosol Performances.

An amount of powder for inhalation was loaded in a multidose dry powderinhaler (Pulvinal®—Chiesi Pharmaceutical SpA, Italy).

The evaluation of the aerosol performances was performed by using amodified Twin Stage Impinger apparatus, TSI (Apparatus of type A for theaerodynamic evaluation of fine particles described in FU IX, 4°supplement 1996). The equipment consists of two different glasselements, mutually connected to form two chambers capable of separatingthe powder for inhalation depending on its aerodynamic size; thechambers are referred to as higher (stage 1) and lower (stage 2)separation chambers, respectively. A rubber adaptor secures theconnection with the inhaler containing the powder. The apparatus isconnected to a vacuum pump which produces an air flow through theseparation chambers and the connected inhaler. Upon actuation of thepump, the air flow carries the particles of the powder mixture, causingthem to deposit in the two chambers depending on their aerodynamicdiameter. The apparatus used were modified in the Stage 1 Jet in orderto obtained an aerodynamic diameter limit value, dae, of 5 μm at an airflow of 30 l/min, that is considered the relevant flow rate forPulvinal® device. Particles with higher dae deposit in Stage 1 andparticles with lower dae in Stage 2. In both stages, a minimum volume ofsolvent is used (30 ml in Stage 2 and 7 ml in Stage 1) to preventparticles from adhering to the walls of the apparatus and to promote therecovery thereof.

The determination of the aerosol performances of the mixture obtainedaccording to the preparation process a) was carried out with the TSIapplying an air flow rate of 30 1/min for 8 seconds.

After nebulization of 10 doses, the Twin Stage Impinger was disassembledand the amounts of drug deposited in the two separation chambers wererecovered by washing with a solvent mixture, then diluted to a volume of100 and 50 ml in two volumetric flasks, one for Stage 1 and one forStage 2, respectively. The amounts of active ingredient collected in thetwo volumetric flasks were then determined by High-Performance LiquidChromatography (HPLC). The following parameters, were calculated: i) theshot weight as mean expressed as mean and relative standard deviation(RSD) ii) the fine particle dose (FPD which is the amount of drug foundin stage 2 of TSI; iii) the emitted dose which is the amount of drugdelivered from the device recovered in stage 1+stage 2; iv) the fineparticle fraction (FPF) which is the percentage of the emitted dosereaching the stage 2 of TSI.

The results in terms of aerosol performances are reported in Table 3.

TABLE 3 Aerosol performances Shot weight Emitted dose FPD FPF mg (%) μgμg % 20.0 (7.8) 9.40 4.44 47.2

The formulation of the invention shows very good flow properties asdemonstrated by the Carr index; this parameter is very important toobtain consistency of the delivered dose when a multi-dose dry powderinhalers with powder reservoir is used. The aerosol performance of theformulation is very good as well with about 50% of the drug reaching thestage 2 of the TSI.

EXAMPLE 2 Hard-Pellet Formulation Containing Coarse Lactose (CapsuLac212-355 μm), a Micronized Pre-blend Lactose/Magnesium Stearate MixtureObtained by Ball Milling and Formoterol Fumarate as Active Ingredient

Blend A was prepared as described in the Example 1 but using α-lactosemonohydrate SorboLac 400 with a starting particle size below 30 μm (d(v,0.5) of about 10 μm) and carrying out the co-micronisation in a ballmilling apparatus for 2 hours.

Blend B was prepared according to the Example 1 but after mixing for 6mins and then screening through a 355 μm sieve.

The hard pellet final formulation was prepared according to the Example1.

The particle size distribution, the water contact angle and the degreeof coating for the micronized mixture (blend A), and the uniformity ofdistribution of the active ingredient for the final formulation (blendB), determined as previously described, are reported in Table 4.

Analogous results were achieved after preparing blend B by mixing for 4hours without screening through a sieve.

TABLE 4 Characterisation of blends A and B Micronised mixture (blend A)Particle size distribution (μm) Malvern d (v, 0.1)  0.72 μm d (v, 0.5) 2.69 μm d (v, 0.9) 21.98 μm water contact angle   52° degree of coating  25% Final formulation (blend B) Uniformity of distribution of theactive ingredient Mean = 11.84 μg  RSD = 1.83%

The in-vitro performances, determined as previously described, arereported in Table 5.

TABLE 5 Aerosol performances Shot weight Emitted dose FPD FPF mg (%) μgμg % 20.8 (6.9) 8.57 4.28 49.9

As it can be appreciated from the results, also such formulation showexcellent characteristics either in terms of flowability properties andin terms of aerosol performances.

EXAMPLE 3 Determination of the Suitable Amount of Magnesium Stearate tobe Added in the Formulation

Samples of pre-blends were prepared as described in Example 2 in a ballmilling apparatus for 2 hours using α-Lactose monohydrate SorboLac 400(Meggle microtose) with a starting particle size below 30 μm (d(v, 0.5)of about 10 μm) and magnesium stearate with a starting particle size of3 to 35 μm (d(v, 0.5) of about 10 μm) in the ratio 98:2, 95:5 and 90:10percent by weight (blends A).

Blends B and the hard pellet final formulation were prepared aspreviously described; the amount of magnesium stearate in the finalformulations turns out to be 0.3, 0.75 and 1.5 percent by weight,respectively. The uniformity of distribution of active ingredient andthe in-vitro aerosol performance were determined as previouslydescribed. The results obtained are reported in Table 6.

TABLE 6 Uniformity of distribution and in-vitro aerosol performances Mgstearate Mg stearate Mg stearate 0.3% 0.75% 1.5% Content uniformity Mean(μg) 11.84 — — RSD (%) 1.83 — — Shot weight Mean (mg) 20.8 24.7 23.0 RSD(%) 6.9 6.5 2.4 Emitted dose (μg) 8.57 10.1 11.1 FPD (μg) 4.28 3.5 3.6FPF (%) 49.9 35 32

In all cases, good performances in terms of fine particle dose areobtained, in particular with 0.3 percent by weight of magnesium stearatein the final formulation.

EXAMPLE 4 Ordered Mixtures Powder Formulations

Powders mixtures were prepared by mixing of commercially availableα-lactose monohydrate with different particle size and formoterolfumarate to obtain a ratio of 12 μg of active to 20 mg of carrier.Blending was carried out in glass mortar for 30 mins. The uniformity ofdistribution of active ingredient and the in-vitro aerosol performanceswere determined as previously described. The results are reported InTable 7.

TABLE 7 Uniformity of distribution and in-vitro aerosol performancesSpherolac Spherolac Pharmatose 100 100 Spherolac 100 325 M (63-90 μm)(90-150 μm) (150-250 μm) (30-100 μm) Content uniformity Mean μg) 11.8911.81 12.98 11.90 RSD (%) 3.88 2.17 9.03 10.10 Shot weight Mean (mg)25.28 25.23 22.02 22.40 RSD (%) 7.73 3.39 6.93 22.00 Emitted dose 11.1010.30 8.50 7.80 (μg) FPD (μg) 1.40 0.70 0.60 1.20 FPF (%) 12.6 6.8 7.115.4

The results indicate that, upon preparation of ordered mixturescontaining formoterol fumarate as active ingredient according to theteaching of the prior art, the performances of the formulations are verypoor.

EXAMPLE 5 Powders Formulations Containing Different Amounts of FineLactose Particles

Carrier A—α-Lactose monohydrate Spherolac 100 (90-150 μm) and Sorbolac400 with a particle size below 30 μm (d(v, 0.5) of about 10 μm) in theratio 95:5 percent by weight were mixed in a mortar for 15 mins.

Carrier B—α-Lactose monohydrate Spherolac 100 (90-150 μm) and micronisedlactose (particle size below 5 μm ) in the ratio 95:5 w/w were mixed ina mortar for 15 mins.

Carrier C—α-Lactose monohydrate Spherolac 100 (150-250 μm) and Sorbolac400 with a particle size below 30 μm (d(v, 0.5) of about 10 μm) in theratio 95:5 percent by weight were mixed in a mortar for 30 mins.

Carrier D—α-Lactose monohydrate Spherolac 100 (150-250 μm) and Sorbolac400 particle size below 30 μm (d(v, 0.5) of about 10 μm) in the ratio90:10 percent by weight were mixed in a mortar for 30 mins.

In the case of all the formulations tested, the carriers were mixed withformoterol fumarate in mortar for 15 mins to obtain a ratio of 12 μg ofactive to 25 mg of carrier.

The results in terms of content uniformity and in-vitro aerosolperformances are reported in Table 8.

TABLE 8 Content uniformity and in-vitro aerosol performances Carrier ACarrier B Carrier C Carrier D Content uniformity Mean (μg) 10.96 10.5011.86 — RSD (%) 1.80 15.01 7.10 — Shot weight Mean (mg) 23.46 25.29 25.719.53 RSD (%) 51.43 4.19 3.77 32.02 Emitted dose (μg) 10.40 9.5 10.15.92 FPD (μg) 1.60 2.3 2.3 1.30 FPF (%) 15.8 24.4 22.68 21.6

The results indicate that the performances of such formulations as wellare very poor.

EXAMPLE 6 “Hard-Pellet Formulation Containing Coarse Lactose (PrismaLac40 Fraction below 355 μm) and Fine Lactose”

α-Lactose monohydrate PrismaLac 40 with a particle size below 355 μm andSorbolac 400 with a particle size below 30 μm (d(v, 0.5) of about 10 μm)in the ratio 60:40 percent by weight were first manually agitated for 10mins to promote aggregation and then blended in a Turbula mixer for 30mins at 42 r.p.m. The spheronised particles were mixed with formoterolfumarate in a Turbula mixer for 30 mins at 42 r.p.m. to obtain a ratioof 12 μg of active to 15 mg of carrier.

The results in terms of uniformity of distribution of active ingredientand in-vitro aerosol performances are reported in Table 9.

TABLE 9 Uniformity of distribution of active ingredient and in-vitroaerosol performances Spheronised particles Content uniformity Mean (μg)11.90 RSD (%) 18.46 Shot weight Mean (mg) 18.10 RSD (%) 6.80 Emitteddose (μg) 11.10 FPD (μg) 2.10 FPF (%) 18.9

The results indicate that the formulation without magnesium stearate hasvery poor performance.

EXAMPLE 7 Effect of the Addition of Magnesium Stearate by Simple Mixing

Formulation A—α-Lactose monohydrate Pharmatose 325 M (30-100 μm) andmagnesium stearate in the ratio 99.75:0.25 percent by weight wereblended in a Turbula mixer for 2 hours at 42 r.p.m. The blend was mixedwith formoterol fumarate in a Turbula mixer for 30 mins at 42 r.p.m. toobtain a ratio of 12 μg of active to 25 mg of carrier.Formulation B—as reported above but α-Lactose monohydrate SpheroLac 100(90-150 μm) instead of Pharmatose 325 M.Formulation C—α-Lactose monohydrate PrismaLac 40 (with a particle sizebelow 355 μm) and micronised lactose with a particle size below 5 μm inthe ratio 40:60 percent by weight were mixed in a Turbula mixer for 60mins at 42 r.p.m. 99.75 percent by weight of the resulting blend and0.25 percent by weight of magnesium stearate were mixed in a Turbulamixer for 60 mins at 42 r.p.m. The resulting blend was finally mixedwith formoterol fumarate in a Turbula mixer for 30 mins at 42 r.p.m. toobtain a ratio of 12 μg of active to 15 mg of carrier.Formulation D—Sorbolac 400 with a particle size below 30 μm (d(v, 0.5)of about 10 μm) and magnesium stearate in the ratio 98: 2 percent byweight were mixed in a high shear mixer for 120 mins (blend A). 85%percent by weight α-lactose monohydrate CapsuLac (212-355 μm) and 15%percent by weight of blend A were mixed in Turbula for 2 hours at 42r.p.m. (blend B); the amount of magnesium stearate in the finalformulation is 0.3 percent by weight. Micronised formoterol fumarate wasplaced on the top of blend B and mixed in a Turbula mixer for 10 mins at42 r.p.m. to obtain a ratio of 12 μg of active to 20 mg of carrier.Formulation E—Micronized lactose with a particle size below 10 μm (d(v,0.5) of about 3 μm) and magnesium stearate in the ratio 98: 2 percent byweight were mixed in a Sigma Blade mixer for 60 mins (blend A). 85percent by weight of α-lactose monohydrate CapsuLac (212-355 μm) and 15percent by weight of blend A were mixed in Turbula for 2 h at 42 r.p.m.(blend B); the amount of magnesium stearate in the final formulation is0.3 percent by weight. Micronised formoterol fumarate was placed on thetop of blend B and mixed in a Turbula mixer for 10 mins at 42 r.p.m. toobtain a ratio of 12 μg of active to 20 mg of carrier.

The results in terms of uniformity of distribution of active ingredientand in-vitro aerosol performances are reported in Table 10.

TABLE 10 Uniformity of distribution of active ingredient and in-vitroaerosol performances Formu- Formu- Formu- Formu- Formu- lations lationslations lations lations A B C D E Content uniformity Mean (μg) 7.9610.50 9.10 10.68 11.32 RSD (%) 2.16 8.30 24.90 2.80 3.0 Shot weight Mean(mg) 24.10 26.50 12.50 22.07 21.87 RSD (%) 34.60 8.20 15.30 2.50 4.0Emitted dose (μg) 6.10 7.60 9.60 8.60 9.93 FPD (μg) 0.60 0.90 1.60 3.384.80 FPF (%) 9.8 11.8 16.7 39.3 48.37

Formulations were magnesium stearate is added, by simple mixing, to thetotal amount of lactose (formulations A-B-C) show very poor performance;no significant differences in the performance of the formulations wereobserved using lactose of different particle size.

Formulations were magnesium stearate is added by a high energy mixing toa small amount of fine lactose (blend A of the formulations D and E)show a significant increase in the performances. In addition, theparticle size of the fine lactose used has a significant effect on thedeaggregation properties of the final formulation; in fact, formulationE prepared using a micronized lactose shows a significant improvedperformance compared with formulation D.

EXAMPLE 8 Effect of the Amount of Micronized Pre-Blend in the FinalFormulation

αLactose monohydrate SpheroLac 100 (Meggle EP D30) with a startingparticle size of 50 to 400 μm (d(v, 0.5) of about 170 μm) and magnesiumstearate with a starting particle size of 3 to 35 μm (d(v, 0.5) of about10 μm) in the ratio 98:2 percent by weight were co-milled in a jet millapparatus (blend A) Different ratios of α-lactose monohydrate Capsulac(212-355 μm) and blend A were placed in a stainless steel container andmixed in a Turbula mixer for four hours at 32 r.p.m. (blends B)

Micronised formoterol fumarate was placed on the top of blends B andmixed in a Turbula mixer for 30 mins at 32 r.p.m. to obtain a ratio of12 μg of active to 20 mg total mixture. The amount of magnesium stearatein the final formulation ranges between 0.05 and 0.6 percent by weight.

The results in terms of uniformity of distribution of active ingredientand in-vitro aerosol performances are reported in Table 11.

TABLE 11 Uniformity of distribution of active ingredient and in-vivoaerosol performance Ratio Ratio Ratio Ratio Ratio Ratio 97.5:2.5 95:592.5:7.5 90:10 80:20 70:30 Content uniformity Mean (μg) 11.29 12.2511.53 11.93 11.96 12.00 RSD (%) 3.8 5.7 1.5 2.5 2.0 2.0 Shot weight Mean(mg) 19.27 20.26 20.38 21.05 22.39 22.48 RSD (%) 4.7 3.3 3.2 4.3 3.5 3.7Emitted dose (μg) 10.58 9.20 10.65 9.18 9.63 9.88 FPD (μg) 4.18 5.106.78 5.9 5.33 5.28 FPF (%) 39.4 55.4 63.6 64.3 55.3 53.4

The results indicate that the performances of all the formulations aregood.

EXAMPLE 9 Hard-Pellet Formulation Containing Coarse Lactose (CapsuLac212-355 μm), a Micronized Pre-Blend Lactose/magnesium Stearate M by JetMilling and Budesonide as Active Ingredient

Blends A and B were prepared as described in the Example 1.

Micronised budesonide was added to the blend B and mixed in a Turbulamixer for 30 mins at 42 r.p.m. to obtain a ratio of 200 μg of active to20 mg of carrier; the amount of magnesium stearate in the finalformulation is 0.3 percent by weight. The final formulation (hard pelletformulation) was left to stand for 10 mins.

The results in terms of uniformity of distribution of active ingredientand in-vitro aerosol performances are reported in Table 12.

TABLE 12 Uniformity of distribution of active ingredient and in-vitroaerosol performances. Content uniformity Mean (μg) 201.60 RSD (%) 1.60Shot weight Mean (mg) 19.47 RSD (%) 3.90 Emitted dose (μg) 178.10 FPD(μg) 71.6 FPF (%) 40.3

The results demonstrate that the teaching of the present invention couldalso be applied to the preparation of a powdery formulation ofbudesonide provided of good performances in term of fine particlefraction.

EXAMPLE 10 Formulation Containing Lactose 90-150 μm, a MicronizedPre-Blend Lactose/magnesium Stearate Mixture Obtained by Jet Milling andFormoterol as Active Ingredient

α-Lactose monohydrate SpheroLac 100 (Meggle EP D30) with a startingparticle size of 50 to 400 μm (d(v, 0.5) of about 170 μm) and magnesiumstearate with a starting particle size of 3 to 35 μm (d(v, 0.5) of about10 μm) in the ratio 98:2 percent by weight were co-milled in a jet millapparatus (blend A).

92.5 percent by weight of α-lactose monohydrate Spherolac with astarting particle size of 90 to 150 μm (d(v, 0.5 of about 145 μm) and7.5 percent by weight of blend A were placed in a stainless steelcontainer and mixed in a Turbula mixer for four hours at 32 r.p.m.(blends B)

Micronised formoterol fumarate was placed on the top of blends B andmixed in a Turbula mixer for 30 mins at 32 r.p.m. to obtain a ratio of12 μg of active to 20 mg total mixture. The amount of magnesium stearatein the final formulation is 0.15 percent by weight.

The results in terms of uniformity of distribution of active ingredientand in-vitro aerosol performances are reported in Table 13.

TABLE 13 Uniformity of distribution of active ingredient and in-vitroaerosol performances. Content uniformity Mean (μg) 11.75 RSD (%) 1.50Shot weight Mean (mg) — RSD (%) — Emitted dose (μg) — FPD (μg) 5.71 FPF(%) 45.2

From the reported results, it can be appreciated that, as long as thefraction of fine particles is less than 10 percent by weight, theperformances of a formulation containing standard lactose as coarsecarrier fraction and a fine particle fraction excipient obtained eitherby co-milling or by co-mixing, are very good.

EXAMPLE 11 Hard-Pellet Formulation Containing Coarse Lactose (CapsuLac212-355 μm), a Micronized Pre-Blend Lactose/magnesium Stearate MixtureObtained by Jet Milling and the Combination Formoterol/beclomethasoneDipropionate (BDP) as Active Ingredient

Blends A and B were prepared as described in the Example 1.

Micronised formoterol and BDP were added to the blend B and mixed in aTurbula mixer for 30 mins at 42 r.p.m. to obtain a ratio of 12 μg and200 μg of active, respectively, to 20 mg of carrier. The amount ofmagnesium stearate in the final formulation is 0.3 percent by weight.The final formulation (hard pellet formulation) was left to stand for 10mins.

The results in terms of uniformity of distribution of the activeingredients and in-vitro aerosol performances are reported in Table 14.

TABLE 14 Uniformity of distribution of the active ingredients andin-vitro aerosol performances. Content uniformity Mean formoterol (μg)11.93 RSD (%) 1.4 Mean BDP (μg) 190.0 RSD (%) 1.1 FPF formoterol (%)47.2 FPF BDP (%) 40.4

The results indicate that, even in presence of a combination of activeingredients, the performances of the formulation are very good.

EXAMPLE 12 Effect of the Time of Mixing

Different blends were prepared by co-mixing CapsuLac 212-355 μm,micronized lactose with a particle size below 10 μm (d(v, 0.5) of about3 μm) and magnesium stearate in the ratio 89.8:10:0.2 percent by weight,in a Turbula mixer (32 r.p.m.) at increasing mixing time (1, 2 and 4hours).

Micronised formoterol fumarate was placed on the top of each blend andmixed in a Turbula mixer for 30 mins at 32 r.p.m. to obtain a ratio of12 μg of active to 20 mg total mixture.

The results in terms of fine particle fraction (FPF) are reported inTable 15.

TABLE 15 Effect of the mixing time on FPF Time of mixing Fine particlefraction (%) 1 hour 21.0 2 hours 34.2 4 hours 40.5

The results indicate that good performances in terms of fine particlefraction are achieved after mixing for at least two hours.

1. A medicinal powder, comprising: i) a fraction of fine particles,comprising particles of a physiologically acceptable excipient andparticles of magnesium stearate, said fraction of fine particles havinga mean particle size of less than 35 μm; ii) a fraction of coarseparticles, comprising particles of a physiologically acceptable carrierhaving a particle size of at least 100 μm; and iii) one or more activeingredient in micronised form selected from the group consisting ofbudesonide and its epimers, formoterol and its stereoisomers, TA 2005and its stereoisomers, salts thereof, and mixtures thereof, wherein:said fraction of fine particles (i) comprises said physiologicallyacceptable excipient in an amount of 90 to 99 percent by weight and saidmagnesium stearate in an amount of 1 to 10 percent by weight; and saidfraction of fine particles and said fraction of coarse particles arepresent in a weight ratio of between 5:95 and 30:70.
 2. A powderaccording to claim 1, wherein said active ingredient is the 22 R epimerof budesonide.
 3. A powder according to claim 1, wherein said activeingredient is a combination of formoterol or TA-2005 with (a) a memberselected from budesonide and its epimers and (b) beclomethasonedipropionate.
 4. A powder according to claim 1, wherein said particlesof magnesium stearate partially coat the surface of either saidparticles of said physiologically acceptable excipient or said particlesof said physiologically acceptable carrier.
 5. A powder according toclaim 1, wherein said fraction of fine particles has a particle size ofless than 15 μm.
 6. A powder according to claim 1, wherein saidparticles of said physiologically acceptable carrier have a particlesize of at least 175 μm, and said fraction of fine particles and saidfraction of coarse particles are present in a weight ratio between 10:90and 20:80.
 7. A powder according to claim 1, wherein said particles ofsaid physiologically acceptable carrier have a fissure index of at least1.25.
 8. A powder according to claim 1, wherein said physiologicallyacceptable excipient is one or more crystalline sugars.
 9. A powderaccording to claim 1, wherein said physiologically acceptable excipientis α-lactose monohydrate.
 10. A powder according to claim 1, whereinsaid fraction of coarse particles has a particle size of at least 175μm.
 11. A powder according to claim 1, wherein said fraction of fineparticles comprises said physiologically acceptable excipient in anamount of about 98 percent by weight and said magnesium stearate in anamount of about 2 percent by weight.
 12. A powder according to claim 1,wherein said fraction of fine particles and said fraction of coarseparticles are present in a weight ratio between 10:90 and 20:80.
 13. Apowder according to claim 1, wherein said physiologically acceptablecarrier comprises at least one crystalline sugar.
 14. A powder accordingto claim 1, wherein said physiologically acceptable carrier compriseslactose.
 15. A powder according to claim 1, wherein said physiologicallyacceptable carrier comprises α-lactose monohydrate.
 16. A powderaccording to claim 1, wherein said magnesium stearate is present in anamount of 0.02 to 1.5% by weight, based on the total weight of saidpowder.
 17. A powder according to claim 1, wherein said magnesiumstearate is present in an amount of 0.05 to 1% by weight, based on thetotal weight of said powder.
 18. A powder according to claim 1, whereinsaid magnesium stearate is present in an amount of 0.1 to 0.6% byweight, based on the total weight of said powder.
 19. A powder accordingto claim 1, wherein said magnesium stearate is present in an amount of0.2 to 0.4% by weight, based on the total weight of said powder.
 20. Apowder according to claim 1, which is prepared by a process comprising:a) co-micronising particles of said physiologically acceptable excipientand particles of said magnesium stearate to reduce the particle size ofsaid physiologically acceptable excipient and said magnesium stearateand to obtain a mixture in which said particles of said physiologicallyacceptable excipient are coated with said magnesium stearate; b)spheronising said mixture by mixing said mixture with said particles ofsaid physiologically acceptable carrier such that particles of saidmixture adhere to the surface of said particles of said physiologicallyacceptable carrier, to obtain speronised particles; c) mixing saidactive ingredient in micronized form with said spheronised particles.21. A powder according to claim 20, wherein said co-micronising iscarried out by milling.
 22. A powder according to claim 21, wherein saidmilling is carried out with a jet mill.
 23. A powder according to claim1, which is prepared by a process comprising: a) mixing in a high-energymixer particles of said physiologically acceptable excipient having astarting particle size of less than 35 μm and particles of saidmagnesium stearate to obtain a mixture in which said particles of saidmagnesium stearate partially coat the surface of said particles of saidphysiologically acceptable excipient; b) spheronising said mixture bymixing said mixture with particles of said physiologically acceptablecarrier such that particles of said mixture adhere to the surface ofsaid particles of said physiologically acceptable carrier, to obtainspheronised particles; and c) mixing said active ingredient particles inmicronised form with said spheronised particles.
 24. A powder accordingto claim 23, wherein said particles of said physiologically acceptableexcipient which are mixed with said magnesium stearate have a startingparticle size of less than 15 μm.
 25. A powder according to claim 1,which is prepared by a process comprising: a) co-mixing particles ofsaid physiologically acceptable carrier, particles of said magnesiumstearate and particles of said physiologically acceptable excipient, toobtain a mixture; and b) mixing said active ingredient in micronisedform with said mixture, wherein said particles of said physiologicallyacceptable carrier have a particle size of at least 175 μm and saidco-mixing is carried out for at least two hours.
 26. A powder accordingto claim 1, which is in the form of spherical or semispherical unitshaving a core of coarse particles.
 27. A process for making a powderaccording to claim 1, said process comprising: a) co-micronisingparticles of said physiologically acceptable excipient and particles ofsaid magnesium stearate to reduce the particle size of saidphysiologically acceptable excipient and said magnesium stearate and toobtain a mixture in which said particles of said physiologicallyacceptable excipient are coated with said magnesium stearate; b)spheronising said mixture by mixing said mixture with said particles ofsaid physiologically acceptable carrier such that particles of saidmixture adhere to the surface of said particles of said physiologicallyacceptable carrier, to obtain speronised particles; and c) mixing saidactive ingredient in micronized form with said spheronised particles.28. A process according to claim 27, wherein said co-micronising iscarried out by milling.
 29. A process according to claim 28, whereinsaid milling is carried out with a jet mill.
 30. A process for making apowder according to claim 1, said process comprising: a) mixing in ahigh-energy mixer particles of said physiologically acceptable excipienthaving a starting particle size of less than 35 μm and particles of saidmagnesium stearate to obtain a mixture in which said particles of saidmagnesium stearate partially coat the surface of said particles of saidphysiologically acceptable excipient; b) spheronising said mixture bymixing said mixture with particles of said physiologically acceptablecarrier such that particles of said mixture adhere to the surface ofsaid particles of said physiologically acceptable carrier, to obtainspheronised particles; and c) mixing said active ingredient inmicronised form with said spheronised particles.
 31. A process accordingto claim 30, wherein said particles of said physiologically acceptableexcipient which are mixed with said magnesium stearate have a startingparticle size of less than 15 μm.
 32. A process of making a powderaccording to claim 1, said process comprising: a) co-mixing particles ofsaid physiologically acceptable carrier, particles of said magnesiumstearate and particles of said physiologically acceptable excipient, toobtain a mixture; and b) mixing said active ingredient in micronisedform with said mixture, wherein said particles of said physiologicallyacceptable carrier have a particle size of at least 175 μm and saidco-mixing is carried out for at least two hours.